Process for the production of estrogenic octahydrophenanthrene carboxylic acids



Patented June 14, 1960 PROCESS FOR THE PRODUCTION OF ESTRO- GENIC OCTAHYDROPHENANTI-IRENE CAR- BOXYLIC ACIDS lVIiroslav Protiva, No. 910 Novorosijska, and Jii'i Jilek, No. 3 Krlzovnicha, Prague, Czechoslovakia US. patent application Ser. No. 594,664, now abandoned, describes new alicyclic lactones having the general formula R1 C (I) wherein R is an alkoxy radical, particularly methoxy, R the methyl group and R a lower alkyl radical, particularly the ethyl group, R being replaceable, if desired, by a hydroxyl group. These alicyclic lactones were to be used as intermediates for preparing some estrogenically active octahydrophenanthrene derivatives. A method of preparing such octahydrophenanthrene derivatives accordingly forms the main object of the present invention.

The invention is based on the determination that alicyclic lactones of the Formula (I) may be converted by heating with catalysts of the Friedel-Crafts type, such as with aluminum chloride, boron trifluoride or tin tetrachloride, in the presence of free hydrogen halogenides, into 1,2,3,4,9,10,11,12-octahydrophenanthrene-Z-carboxylic acids of the general Formula (II), wherein R and R possess the same meaning as above, and R signifies either an alkoxy radical, as above, or a hydroxyl group, since the original alkoxy group R may in some cases be partially dealkylated during the reaction. The compounds in which R is a hydroxyl group are also very estrogenically active and may be prepared in pure state and high yields by intentional dealkylation, e.g. by heating with pyridine hydrochloride.

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(H) The reaction is advantageously carried out either in an appropriate non-polar solvent or without any solvent. The most advantageous embodiment of the present invention is the introduction of dry hydrogen chloride into aboilingsolution of said alicyclic lactones in benzene with a catalyst suspended therein.

The reaction always yields a mixture of stereoisomeric acids of the Formula 11, containing, in addition to compounds in which R is an alkoxy radical, also dealkylated products in which R is a hydroxyl group. In a further development of the present invention it has been found that such mixture may be resolved into its components by methylation, e.g. with dimethyl sulfate in an aqueous alkaline solution and then by heating it with excess di-' nited States Patent Ofice azomethane in ether solution, followed by vacuum fractionation. The methyl esters of the general Formula 111, wherein the substituents possess the same meaning as in the Formulas I and II, may be vacuum distilled without decomposition. The mixture of 0 O O CH:

the methyl esters III may also be fractioned chromatographically.

The purified methyl esters (III) may be converted into free acids (II) by alkaline saponification under drastic conditions which are required because of the considerable steric protection of the carbomethoxyl in the esters (H1). The best method consists in heating said methyl esters with excess potassium hydroxide, wetted with alcohol and water, at a temperature of 170-l80 C. After dissolving the molten mass thus formed and removing the undissolved neutral components, the acids (II) are precipitated by acidification with an inorganic acid, such as hydrochloric acid. The purified products thus obtained are as yet amorphous and possess a comparatively low melting point, so that they cannot be directly recrystallized. For further fractionation it is possible to utilize the difierent solubility of the sodium salts in water or in moderately alkaline aqueous solutions, such as in an aqueous sodium carbonate solution. In this way it is possible to obtain crystalline sodium salts of the acids (11), which may be worked up by acidification and usual further treatment to crystallin and stereochemically uniform acids (H).

As mentioned above, a partial dealkylation occurs during the isomerization of the lactones (I) to acids (II), if R is an alkoxy group. The dealkylation products are also very interesting and may be prepared in pure form by intentional dealkylation by heating them with a hydrochloride of a nitrogen base, such as of pyridine.

l,2,3,4,9,10,ll,;l2 octahydrophenanthrene 2 car boxylic acids of the Formula H possess high biological activity of the female hormone type. Some compounds of this series even surpass in their estrogenic activity natural female hormones, e.g. estradiol and estrone; in comparison with them, however, they possess the advantage of equal effectiveness both in parenteral and oral application. They may therefore be utilized in treating some hormonal disturbances or other diseases where estrogens are usually dispensed.

Example 1 Gaseous dry hydrogen chloride introduced into a boiling suspension of 30 grams of anhydrous aluminum chloride in 240 cc. of dry thiophene-free benzene. Simultaneously a solution of 10.0 grams of lactone of 1-(2- m-methoxy phenylethyl)-2-ethyl-3 methylcyclohexanol- 3-carboxylic acid in' an additional 150 cc. of benzene is added dropwise during one hour while stirring. Thereafter the reaction mixture is heated and saturated with hydrogen chloride for an additional 90 minutes. The mixture is then left standing overnight. Then 300 millilitres of 3 N-hydrochloric acid are dropped in while stirring and cooling with ice. The precipitate is sucked OE and washed with water. After drying over phosphoric anhydride the yield of the raw acid amounts to 8.0 grams. The product melts not sharp at -95 C.

The raw acid mixture thus obtained is dissolved in 50 cc. of ether and it is then methylated-with an ether hydroxy acids mixture.

- e e e e A solution of diazomethane, which is formed from 30 grams of N-nitroso-p-toluene sulfomethylamide accordestrogenic activity. It is the semihydrate of 1-ethyl-2- methyl 7 hydroxy-1,2,3,4,9,10,-11,12-octahydrophenaning to De Boer and Backer (Rec. trav. chim. 73, 233,

1954). Themixture is-left standing overnight and then the excess of diazomethaneis decomposed by adding)? millilitres of. glacial acetic acid drop by drop. Thes'ol'ution-is filteredthrough a columntof 50 grams of alumi num oxide and the filtrate is evaporated. The residue is 8.23 grams ofraw methyl esters of the methoxyand By vacuum distillation from a Hickman still one obtains 6.4 grams of a fraction boiling at 190-205 C./0.l-0.2 mm. Hg; according to the elementary analysis this fraction consists mainly of the methyl esters of the methoxy acids (HI), contaminated with a minor amount of methyl esters of the hydroxy acids. The fraction is dissolved in 100 millilitres of ether and the solution is extracted by shaking it two times,

each timewith 30 millilitres often percent potassium hy- 1 droxide solution in order to remove compounds with a free phenolic group. The alkaline extract is then methylated 'by]heating with '10 grams of dimethyl sul fate ona water-bath'for three hours while stirring. From the obtained reaction mixture a further amount of methoxy acidrnethyl ester is recovered in usual manner. The'ether solution containing 6.1 grams of a mixture of methyl esters (H1) is evaporated and the'residue is chromatographed on a 200 grams neutral alumina'cola petroleum ether-benzene mixture (1:1). It may be redistilled, if desired. 7 Its boiling point is l85 C. at

V 0.1 mm. Hg pressure.

2.0 grams'of the product are dissolved in 8 millilitres of ethanol and" the solution is added to a mixture of 8 grams of potassium hydroxide with 4 millilitres of water.

The whole isheated in, an open vessel on, an oil-bath at such a rate that the'temperatu're reaches 170-l80 C. during'about 'ZOmiriutes. Then the mixture is partially cooled down, 6 millilitresofethanolare added and the whole is heated again'until allthe ethanol is evaporated and'theternperature of the oil-bath again reaches 'l70' 180 C. The heatin'g'with ethanol-is repeated a total ofifourgtimes. After'ha'ying been cooled down the produsage-purified by extracting it' with 100 millilitres of ether. 1 After having distilled offthe ether dissolved in the aqueous layer, the latter is filtered with active charcoaljcooled down to 5 CI and acidified with concentratedjhydrochloric acid'added dropwise while stirring. The precipitate thus formed is suckedolf, washed with 'Water and dissolved in 80 millilitres of five percent'socarbonate solutionunder slight warming. By cooling. the bulk of the product crystallizes as pure sodium threne-Z-carboxylic acid having the following structural formula:

a V (\kooon .7 v mg g i saturation with dry hydrogen chloride for one hour, and

' umn--(activity '11). The main fraction is eluated'with finally the saturation with hydrogen chloride is maintained for another hour at room temperature. The reaction mixture is then left standing overnight;

The next day 300 millilitres of 3 N-hydrochloric acid are slowly added while stirring and cooling and the whole is left standing overnight again. The separated benzene layer is shaken out with 600 millilitres of five percent sodium hydroxide. The alkaline solution thus obtained is freed from some precipitate and mixed with '20 grams of sodium hydroxide.

After dissolving the latter, 50 millilitres of dimethyl sulfate are added and the mixture is heated for anhour on a boiling water-bath while stirring. After having been cooled down the solution is acidified under constant stirring with concentrated hydroi chloric acid and the precipitate is extracted by shaking out withether. The other solution is dried with anhydroussodium sulfate and evaporated. The residue, obtained inan'amount of 9.0 grams, is dissolved-in millilitres of ether, and into vthis solution a mixture of not" is dissolved in 150 millilitres of water. and the solusaltof one stereoisomer of v1-ethyl-2-methyl-7-methoxyw 300 milligrams of this acidare demethylated by heating with 3.0 grams of pyridine hydrochloride in 4.5 hours at 170-190" C. After haying been cooled down the mixture is 1eached with 30cc, of 3 N-hydrochloric acid and after 12 hours the precipitate is separated by filtration and recrystallized from'ethanol. It melts somewhatunsharply. at about 116 C.l and also possesses high ether and diazomethane is distilled,'this mixture being formed from 2.5 grams of N-nitroso-p-toluene sulfom'ethylamide according to De Boer and Backer (see above). The reaction mixture is kept overnight, the ex cess of diazomethane is decomposed with glacial acetic acid' (4.5 millilitres) and the ether is distilled off. The residue, obtained in an amount of 9.2 grains, is vacuum distilled from a Hickmanstill. There are thus obtained 6.1 grams of methyl esters of stereoisomeric 1-ethyl-2- methyl- 7 methoxy-1,2,3,'4,9,10,11,12-octahydrophenan threne-Z-carboxylic acids, melting at -195 C] A 0.1-0.2 mm. Hg.

The whole amount ofthis product is saponified with '24 grams of potassium hydroxide in the manner described in-Example 1. 5.6 grams of raw free methoxy acids are obtained by' acidification, melting at 50-'60 C. The

product is dissolved, as in the foregoing example, in a soda solution in order to obtain the crystalline sodium salt of a stereoisomer. free 1 ethyl-2-methyl-7-methoxy-1,2,3,4,9;l0,11,12-octahydrophenanthrene-Z-carboxylic acid, melting at 189- 19.0" 0., identical with. the product according to Example 1. v V 7 Some inorganic halogenides of the class of Friedel- Crafts catalysts, easily form free hydrogen halogenides incontact with traces of humidity, e.g. in contact with water vapors contained .in the air. An intentional addition of. free hydrogen halogenides is thus superfluous, if a suliicient amount of sucha catalyst is used. The ex- Pression in the presence of free hydrogen halogenide used above and in the following claims doesnot mean, in consequence, that hydrogen halogenide must be. always introduced a'ssuch.

The salt yields by acidification What is claimed is: 1. In a method of producing compounds having the following general Formula I:' r

wherein R is a methoxy group, and wherein R and R have the same definition as above with a catalyst of the Friedel-Crafts type in the presence of a free hydrogen halide.

2. In a method of producing compounds having the following general Formula I:

--COOR4 wherein R is selected from the group consisting of hydroxyl and methoxy, wherein R is methyl, wherein R is ethyl, and wherein R is hydrogen, the step of heating an alicyclic lactone of the following general Formula II:

wherein R is a methoxy group, and wherein R and R have the same definition as above with a catalyst of the Friedel-Crafts type selected from the group consisting of aluminum chloride, boron trifiuoride and tin tetrachloride in the presence of a free hydrogen halide.

3. In a method of producing a compound having the following general Formula I:

wherein R is hydroxyl, wherein R is methyl, wherein R is ethyl, and wherein R is hydrogen, the step of heatwherein R is methoxy, and wherein R and R have the same definition as above with a catalyst of the Friedel- Crafts type selected from the group consisting of aluminum chloride, boron trifiuoride and tin tetrachloride in the presence of a free hydrogen halide so as to form a mixture of compounds of Formula I wherein R is methoxy and wherein R is hydroxyl; and de-alkylating the thus formed compound wherein R is methoxy by heating the same with pyridine hydrochloride so as to form the compound of Formula I wherein R is hydroxyl.

4. In a method of producing a mixture of compounds having the following general formula I:

COOR| wherein R is hydroxyl and wherein R is methoxy, wherein R is methyl, wherein R is ethyl, and wherein R is hydrogen, the step of heating an alicyclic lactone of the following general Formula II:

wherein R is a methoxy group, and wherein R and R have the same definition as above dissolved in a nonpolar solvent with a catalyst of the Friedel-Orafts type selected from the group consisting of aluminum chloride, boron trifluoride and tin tetrachloride in the presence of a free hydrogen halide.

5. In a method of producing a compound having the following general Formula I:

COOR4 wherein R is methoxy, wherein R is methyl, wherein R is ethyl, and wherein R is hydrogen, the step of heating an alieyclic lactone of the following general Formula H:

wherein R is a methoxy group, and wherein R and R have the same definition as above with a catalyst of the halide so as to form a reaction mixture including'a mixture of said compound of Formula I wherein R is hydrogen and wherein Rl is'hydroxyl and said compound of Formula I wherein Rigis hydrogen and wherein'R is methoxy; methylating said compounds of Formula I wherein R is hydrogen and wherein R is hydroxyl to the corresponding compounds of Formula I wherein R is methyl and wherein R is methoxy so as to form a reaction mass consisting essentially; of the corresponding methoxy methyl ester; fractionating said methoigy methyl esters by vacuum distillation; 'sapon'ifying t h e-; ohtai'ned fractions with'pot'assiu'm hydroxide at elevated tempera tur; and converting the thus obtainedfsaponified products-into the free acids by acidification. 7i T 6. In a method of producing acompo'u'nd having the followingigeneral Formula I: p a

wherein R is methoxy, wherein R is methyl, wherein R is ethyl, and wherein R is hydrogen, the step of heating an alicyclic lactone of the following general FormulaH: I

8 wherein R is a methoxy group, andwherein R- and k h v ingame definitionlasr flbQY w h weta y a fi Frieda-Crafts yp in flie pr sei traw tee hyd e halide so as to form a reaction mixture including a mixture of said compound of'Formula I wherein R 'is hydrogen and whereinzi k gishydroxyl and said compound of Formula I wherein R is hydrogen and wherein R is methoxy; methylatingi said compounds of Formula I wherein R is hydrogen and whereimR is hydroxyl to the corresponding compounds of Formula I wherein R is methyl and wherein R is methoxy so .asto form a reaction mass consisting essentially of the corresponding methoxy methyl esters, fractioning said methoxy methyl .esters References Cited in the file of this patent UNITED STATES PATENTS 2,459,834 Miescher et al Jan. 25, 1949 2,534,466 Miescher et a1. Dec. 19, 1950 2,663,716 Johnson et a1 Dec. 22, 1953 2,732,389 

1. IN A METHOD OF PRODUCING COMPOUNDS HAVING THE FOLLOWING GENERAL FORMULA I: 